Up to 1% of patients with refractory epilepsy die suddenly every year in an unexplained phenomenon called Sudden Unexpected Death in Epilepsy (SUDEP). In 2008 a joint American Epilepsy Society and Epilepsy Foundation convened Task Force recommended hypothesis-driven, prospective, multicenter research into SUDEP with multi-modal seizure parameters including cardiovascular, respiratory, autonomic and biochemical factors. This approach is vital as SUDEP is most likely a seizure related event. In SUDEP, we hypothesize exaggerated supra-pontine seizure influences produce severe autonomic dysfunction manifested as profound hypotension, fatal arrhythmia or apnea. Genetic predisposition and brainstem serotonergic dysregulation may contribute. However, critical barriers to research exist including 1) an annual SUDEP incidence of 0.5-1% making large multi-center studies necessary and 2) the collection and analysis of very large datasets of multi-modal seizure data (video, electroencephalography (EEG), electrocardiography (EKG), blood pressure, O2 & CO2 measurements, sleep data); traditional visual and statistical analyses of these multiple parameters that vary from second to second are very difficult. To overcome these barriers, a sophisticated bio-informatics system is required to acquire, standardize and analyze such data from a wide range of seizure monitoring systems in different centers. The proposed Prevention and Risk Identification of SUDEP Mortality (PRISM) Project will 1) leverage existing expertise and infrastructure at our Center to create a novel, integrated multi-modal data acquisition and management system called MEDCIS (Multi-modality Epilepsy Data Capture and Integration System). Through MEDCIS, we will aim to collect a large scale, multicenter, prospective cohort of epilepsy patients undergoing seizure monitoring. MEDCIS will prospectively create a surveillance register of SUDEP. We will 2) aim to establish capability for comprehensive comparative studies of SUDEP and near-SUDEP cases vs. cohort survivors to ascertain differences in clinical epilepsy and multi-modal physiological seizure data including EEG, EKG, autonomic, cardiovascular, respiration, sleep, endocrine and evoked potential features in order to characterize and quantify seizure induced brainstem dysfunction. 3) A SUDEP brain bank and genetics database will also be established within MEDCIS adding to an existing, substantial collection of material to investigate genetic influences and serotonergic brain dysfunction. The PRISM Project will form the core of a subsequent SUDEP Center Without Walls and will enable multi-disciplinary collaborations in SUDEP research to succeed. Such an approach is the most likely to produce effective SUDEP prevention strategies.